The lack or dysfunction of blood clotting Factor VIII (FVIII) is associated with the bleeding disorder hemophilia A. The treatment of choice for the management of hemophilia A is replacement therapy with plasma-derived or recombinant FVIII (rFVIII) concentrates. It is generally accepted that patients with severe hemophilia A, i.e. with FVIII levels below 1%, are best treated by a prophylactic therapy with the aim of keeping FVIII levels above 1% in-between doses. Taking into account the average half-lives of the various FVIII products in the circulation, this circulating concentration can usually be achieved by administering FVIII two to three times a week. To increase the convenience of current prophylaxis therapy, the development of a next generation product with enhanced pharmacodynamic and pharmacokinetic properties, while maintaining all other product characteristics, is envisaged to allow dosing on a weekly basis.
Therapeutic polypeptide drugs are not only exposed to proteolytic enzymes and neutralizing antibodies, but are also prone to removal from the circulation by receptor-mediated cellular uptake. These events are associated with a reduction in the half-life and circulation time of the applied proteins, thereby limiting their therapeutic effectiveness. Modification of the polypeptide drugs with polymers such as PEG has been shown to protect them from enzymatic degradation and clearance to a significant extent thereby improving their pharmacodynamic and pharmacokinetic profiles. In addition, PEGylation can lead to decreased immunogenicity, increased physical and thermal stability, increased solubility, increased liquid stability, and reduced aggregation.
PEGylation is usually achieved by the covalent attachment of one or more PEG chains per monomer to a polypeptide drug. Stable linkage of PEG to proteins has the disadvantage of decreasing the protein's biological function in an irreversible manner. This can be circumvented by modifying the proteins with a reversibly-linked PEG, which has the potential to dissociate from the protein over time. This type of releasable PEG should allow liberation of the native protein, accompanied with a full regain of the native protein's activity.